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Heterozygous FA2H mutations in autism spectrum disorders.

Scheid I, Maruani A, Huguet G, Leblond CS, Nygren G, Anckarsäter H, Beggiato A, Rastam M, Amsellem F, Gillberg IC, Elmaleh M, Leboyer M, Gillberg C, Betancur C, Coleman M, Hama H, Cook EH, Bourgeron T, Delorme R - BMC Med. Genet. (2013)

Bottom Line: Also, two rare non-synonymous mutations (R113W and R113Q) were reported.Although predictive models suggested that R113W should be a deleterious, we did not find that FA2H activity was affected by expression of the R113W mutation in cultured COS cells.While our results do not support a major role for FA2H coding variants in ASD, a screening of other genes related to myelin synthesis would allow us to better understand the role of non-neuronal elements in ASD susceptibility.

View Article: PubMed Central - HTML - PubMed

Affiliation: Human Genetics and Cognitive Functions, Institut Pasteur, Paris, France. richard.delorme@rdb.aphp.fr.

ABSTRACT

Background: Widespread abnormalities in white matter development are frequently reported in cases of autism spectrum disorders (ASD) and could be involved in the disconnectivity suggested in these disorders. Homozygous mutations in the gene coding for fatty-acid 2-hydroxylase (FA2H), an enzyme involved in myelin synthesis, are associated with complex leukodystrophies, but little is known about the functional impact of heterozygous FA2H mutations. We hypothesized that rare deleterious heterozygous mutations of FA2H might constitute risk factors for ASD.

Methods: We searched deleterious mutations affecting FA2H, by genotyping 1256 independent patients with ASD genotyped using Genome Wide SNP arrays, and also by sequencing in independent set of 186 subjects with ASD and 353 controls. We then explored the impact of the identified mutations by measuring FA2H enzymatic activity and expression, in transfected COS7 cells.

Results: One heterozygous deletion within 16q22.3-q23.1 including FA2H was observed in two siblings who share symptoms of autism and severe cognitive impairment, axial T2-FLAIR weighted MRI posterior periventricular white matter lesions. Also, two rare non-synonymous mutations (R113W and R113Q) were reported. Although predictive models suggested that R113W should be a deleterious, we did not find that FA2H activity was affected by expression of the R113W mutation in cultured COS cells.

Conclusions: While our results do not support a major role for FA2H coding variants in ASD, a screening of other genes related to myelin synthesis would allow us to better understand the role of non-neuronal elements in ASD susceptibility.

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Related in: MedlinePlus

An heterozygous FA2H deletion was identified with the Human 1 M-Duo SNP array from Illumina in the patient AUR139_7. The heterozygous deletion, inherited from the mother and shared by an affected sibling, spans 167.1 kb on chromosome 16q22.3-q23.1, and included FA2H, MLKL and the first two exons of RFWD3. The upper plot shows Log R Ratio (in red) and B allele frequency (in green). QuantiSNP score is represented with a blue line and indicates the deletion size. One heterozygous deletion was previously referenced in the Database of Genomic Variants (chr16:73304298-73370177_hg18 variation_49753) and reported in 3/2026 children from the CHOP cohort. Three patients with developmental delay are reported in DECIPHER (https://decipher.sanger.ac.uk): two carried a deletion (ID: 1694, del chr16:73196749-73363966_hg18; ID: 253240, chr16:71201202-88651780_hg18) and one a duplication (ID: 2564, chr16:72853856-74355880_hg18). Red bars are deletions, and blue bars are duplications.
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Figure 1: An heterozygous FA2H deletion was identified with the Human 1 M-Duo SNP array from Illumina in the patient AUR139_7. The heterozygous deletion, inherited from the mother and shared by an affected sibling, spans 167.1 kb on chromosome 16q22.3-q23.1, and included FA2H, MLKL and the first two exons of RFWD3. The upper plot shows Log R Ratio (in red) and B allele frequency (in green). QuantiSNP score is represented with a blue line and indicates the deletion size. One heterozygous deletion was previously referenced in the Database of Genomic Variants (chr16:73304298-73370177_hg18 variation_49753) and reported in 3/2026 children from the CHOP cohort. Three patients with developmental delay are reported in DECIPHER (https://decipher.sanger.ac.uk): two carried a deletion (ID: 1694, del chr16:73196749-73363966_hg18; ID: 253240, chr16:71201202-88651780_hg18) and one a duplication (ID: 2564, chr16:72853856-74355880_hg18). Red bars are deletions, and blue bars are duplications.

Mentions: Among the 1256 independent patients with ASD genotyped using Illumina SNP arrays [996 from the AGP [12] and 260 from the PARIS study [13]], we detected a heterozygous 167.1 kb deletion within 16q22.3-q23.1 [chr16: 73258900-73426000_hg18] in one patient (AUR139_7) with autism and moderate intellectual disability (see clinical data section for details / Family 1). This CNV, inherited from the non-affected mother (Social Responsiveness Scale total score: 16: compared to a normal value <42; [14]) was shared by his affected sibling (AUR139_6) with autism and severe intellectual disability, and was absent from 5 unaffected siblings (Figure 1). The deletion, including FA2H, MLKL and the first two exons of RFWD3, was validated by qPCR analysis using DNA from an independent blood sample from both parents and the proband (data not shown). No additional rare micro-rearrangement was shared by the two affected siblings.


Heterozygous FA2H mutations in autism spectrum disorders.

Scheid I, Maruani A, Huguet G, Leblond CS, Nygren G, Anckarsäter H, Beggiato A, Rastam M, Amsellem F, Gillberg IC, Elmaleh M, Leboyer M, Gillberg C, Betancur C, Coleman M, Hama H, Cook EH, Bourgeron T, Delorme R - BMC Med. Genet. (2013)

An heterozygous FA2H deletion was identified with the Human 1 M-Duo SNP array from Illumina in the patient AUR139_7. The heterozygous deletion, inherited from the mother and shared by an affected sibling, spans 167.1 kb on chromosome 16q22.3-q23.1, and included FA2H, MLKL and the first two exons of RFWD3. The upper plot shows Log R Ratio (in red) and B allele frequency (in green). QuantiSNP score is represented with a blue line and indicates the deletion size. One heterozygous deletion was previously referenced in the Database of Genomic Variants (chr16:73304298-73370177_hg18 variation_49753) and reported in 3/2026 children from the CHOP cohort. Three patients with developmental delay are reported in DECIPHER (https://decipher.sanger.ac.uk): two carried a deletion (ID: 1694, del chr16:73196749-73363966_hg18; ID: 253240, chr16:71201202-88651780_hg18) and one a duplication (ID: 2564, chr16:72853856-74355880_hg18). Red bars are deletions, and blue bars are duplications.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4219428&req=5

Figure 1: An heterozygous FA2H deletion was identified with the Human 1 M-Duo SNP array from Illumina in the patient AUR139_7. The heterozygous deletion, inherited from the mother and shared by an affected sibling, spans 167.1 kb on chromosome 16q22.3-q23.1, and included FA2H, MLKL and the first two exons of RFWD3. The upper plot shows Log R Ratio (in red) and B allele frequency (in green). QuantiSNP score is represented with a blue line and indicates the deletion size. One heterozygous deletion was previously referenced in the Database of Genomic Variants (chr16:73304298-73370177_hg18 variation_49753) and reported in 3/2026 children from the CHOP cohort. Three patients with developmental delay are reported in DECIPHER (https://decipher.sanger.ac.uk): two carried a deletion (ID: 1694, del chr16:73196749-73363966_hg18; ID: 253240, chr16:71201202-88651780_hg18) and one a duplication (ID: 2564, chr16:72853856-74355880_hg18). Red bars are deletions, and blue bars are duplications.
Mentions: Among the 1256 independent patients with ASD genotyped using Illumina SNP arrays [996 from the AGP [12] and 260 from the PARIS study [13]], we detected a heterozygous 167.1 kb deletion within 16q22.3-q23.1 [chr16: 73258900-73426000_hg18] in one patient (AUR139_7) with autism and moderate intellectual disability (see clinical data section for details / Family 1). This CNV, inherited from the non-affected mother (Social Responsiveness Scale total score: 16: compared to a normal value <42; [14]) was shared by his affected sibling (AUR139_6) with autism and severe intellectual disability, and was absent from 5 unaffected siblings (Figure 1). The deletion, including FA2H, MLKL and the first two exons of RFWD3, was validated by qPCR analysis using DNA from an independent blood sample from both parents and the proband (data not shown). No additional rare micro-rearrangement was shared by the two affected siblings.

Bottom Line: Also, two rare non-synonymous mutations (R113W and R113Q) were reported.Although predictive models suggested that R113W should be a deleterious, we did not find that FA2H activity was affected by expression of the R113W mutation in cultured COS cells.While our results do not support a major role for FA2H coding variants in ASD, a screening of other genes related to myelin synthesis would allow us to better understand the role of non-neuronal elements in ASD susceptibility.

View Article: PubMed Central - HTML - PubMed

Affiliation: Human Genetics and Cognitive Functions, Institut Pasteur, Paris, France. richard.delorme@rdb.aphp.fr.

ABSTRACT

Background: Widespread abnormalities in white matter development are frequently reported in cases of autism spectrum disorders (ASD) and could be involved in the disconnectivity suggested in these disorders. Homozygous mutations in the gene coding for fatty-acid 2-hydroxylase (FA2H), an enzyme involved in myelin synthesis, are associated with complex leukodystrophies, but little is known about the functional impact of heterozygous FA2H mutations. We hypothesized that rare deleterious heterozygous mutations of FA2H might constitute risk factors for ASD.

Methods: We searched deleterious mutations affecting FA2H, by genotyping 1256 independent patients with ASD genotyped using Genome Wide SNP arrays, and also by sequencing in independent set of 186 subjects with ASD and 353 controls. We then explored the impact of the identified mutations by measuring FA2H enzymatic activity and expression, in transfected COS7 cells.

Results: One heterozygous deletion within 16q22.3-q23.1 including FA2H was observed in two siblings who share symptoms of autism and severe cognitive impairment, axial T2-FLAIR weighted MRI posterior periventricular white matter lesions. Also, two rare non-synonymous mutations (R113W and R113Q) were reported. Although predictive models suggested that R113W should be a deleterious, we did not find that FA2H activity was affected by expression of the R113W mutation in cultured COS cells.

Conclusions: While our results do not support a major role for FA2H coding variants in ASD, a screening of other genes related to myelin synthesis would allow us to better understand the role of non-neuronal elements in ASD susceptibility.

Show MeSH
Related in: MedlinePlus